tbuckley/cabot-search huggingface dataset:
Mutant Kras and mTOR crosstalk drives hepatocellular carcinoma development via PEG3/STAT3/BEX2 signaling
Authors: Yuan-Deng Luo, Xiao-Yu Liu, Lei Fang, Hong-Qiang Yu, Yu-Jun Zhang, Min Chen, Lei-Da Zhang, Chuan-Ming Xie
Journal: Theranostics (2022)

Background & Aims: Abnormal activation of mTOR through loss of tuberous sclerosis complex (Tsc) frequently occurs in hepatocellular carcinoma (HCC).Mutant Kras could induce aggressive HCCs.Here, we aim to identify the predictive or prognostic biomarkers for HCC patients with Kras mutant and mTOR hyperactivation, and to provide potential therapeutic approaches for this subtype of HCCs.Methods: We generated transgenic mice in which hepatocytic mTOR was hyperactivated through Tsc1 insufficiency with or without oncogenic Kras G12D .Bioinformatics and gain-or loss-of-function studies were used to illustrate the mechanisms underlying oncogenic pathway alterations.Transcriptional profiling was used to identify biomarker for the subtype of HCC.The therapeutic efficacy of targeting mTOR was tested in a liver orthotropic homogeneous murine model.Results: Oncogenic Kras G12D facilitated mTOR activation via the Mek/Erk/ROS axis, leading to HCC tumorigenesis and metastasis.Inhibition of Mek/Erk enhanced the anticancer effect of mTOR inhibitor via reduction of mTOR activity.Paternally expressed 3 (PEG3) was responsible for Kras/Erk-and mTOR-driven HCC.Elevated PEG3 protein interacted with STAT3 and promoted its transcriptional activity, resulting in the upregulation of proliferation-and metastasis-related proteins.Targeting mTOR significantly inhibited these actions in vitro and in vivo.Moreover, in clinical samples, PEG3 was identified as a new poor prognostic marker for HCC patients with Kras/Erk and mTOR hyperactivation.Conclusion: These findings reveal the underlying mechanism of hepatocytic Kras/Erk-driven mTOR activation and its downstream targets (PEG3 and STAT3) in HCC, identify PEG3 as a new prognostic biomarker for HCC with Kras/Erk and mTOR hyperactivation, and provide a potential therapeutic strategy for this subset of HCC patients.
Normalisation of circulating neutrophil counts after 12 months of elexacaftor-tezacaftor-ivacaftor in patients with advanced cystic fibrosis
Authors: Théo Dhote, Clémence Martin, Lucile Regard, Lucie Pesenti, Reem Kanaan, Nicolas Carlier, Isabelle Honoré, Jennifer Da Silva, Véronique Witko-Sarsat, Pierre-Régis Burgel
Journal: European Respiratory Journal (2022)

<b>In people with cystic fibrosis and advanced lung disease, circulating neutrophils were often elevated under clinically stable conditions. Treatment with elexacaftor-tezacaftor-ivacaftor for 12 months is associated with normalisation of neutrophil counts.</b> http://bit.ly/3gtgDFx
Divergent Actions of Myofibroblast and Myocyte β <sub>2</sub> -Adrenoceptor in Heart Failure and Fibrotic Remodeling
Authors: Bingqing Deng, Yu Zhang, Chaoqun Zhu, Ying Wang, Eric Weatherford, Bing Xu, Xianhui Liu, Simon J. Conway, E. Dale Abel, Yang K. Xiang
Journal: Circulation Research (2022)

Figure.Divergent actions of myofibroblast and myocyte β 2 -adrenoceptor (β 2 AR) in heart failure and fibrotic remodeling.A, Quantification of body weights during 6 months high fat diet (HFD) in β 2 AR-flox and β 2 AR-cKO and fKO transgenic mice.Plasma glucose levels were measured after a 6-hour fast followed by intraperitoneal injection of glucose (1 g/kg), and cardiac function was measured by echocardiography, including ejection fraction (EF), E/A ratio (ratio of the early [E] to late [A] ventricular filling velocities), and isovolumic relaxation time (IVRT).B, Picrosirius-red staining for collagen in heart tissue was imaged and quantified; heart weights were normalized to tibia lengths.C, RNA sequencing analysis of β 2 ARflox, cKO, and fKO mouse hearts after normal chow (NC) and HFD feeding.(Continued )
Differential roles of Aβ42/40, p-tau231 and p-tau217 for Alzheimer’s trial selection and disease monitoring
Authors: Nicholas J. Ashton, Shorena Janelidze, Niklas Mattsson-Carlgren, Alexa Pichet Binette, Olof Strandberg, Wagner S. Brum, Thomas K. Karikari, Fernándo González-Ortiz, Guglielmo Di Molfetta, Francisco J. Meda, Erin M. Jonaitis, Rebecca Langhough Koscik, Karly Cody, Tobey J. Betthauser, Yan Li, Eugeen Vanmechelen, Sebastian Palmqvist, Erik Stomrud, Randall J. Bateman, Henrik Zetterberg, Sterling C. Johnson, Kaj Blennow, Oskar Hansson
Journal: Nature Medicine (2022)

Abstract Blood biomarkers indicative of Alzheimer’s disease (AD) pathology are altered in both preclinical and symptomatic stages of the disease. Distinctive biomarkers may be optimal for the identification of AD pathology or monitoring of disease progression. Blood biomarkers that correlate with changes in cognition and atrophy during the course of the disease could be used in clinical trials to identify successful interventions and thereby accelerate the development of efficient therapies. When disease-modifying treatments become approved for use, efficient blood-based biomarkers might also inform on treatment implementation and management in clinical practice. In the BioFINDER-1 cohort, plasma phosphorylated (p)-tau231 and amyloid-β42/40 ratio were more changed at lower thresholds of amyloid pathology. Longitudinally, however, only p-tau217 demonstrated marked amyloid-dependent changes over 4–6 years in both preclinical and symptomatic stages of the disease, with no such changes observed in p-tau231, p-tau181, amyloid-β42/40, glial acidic fibrillary protein or neurofilament light. Only longitudinal increases of p-tau217 were also associated with clinical deterioration and brain atrophy in preclinical AD. The selective longitudinal increase of p-tau217 and its associations with cognitive decline and atrophy was confirmed in an independent cohort (Wisconsin Registry for Alzheimer’s Prevention). These findings support the differential association of plasma biomarkers with disease development and strongly highlight p-tau217 as a surrogate marker of disease progression in preclinical and prodromal AD, with impact for the development of new disease-modifying treatments.
Prebiotic oligofructose protects against high-fat diet-induced obesity by changing the gut microbiota, intestinal mucus production, glycosylation and secretion
Authors: Paola Paone, Francesco Suriano, Ching Jian, Katri Korpela, Nathalie M. Delzenne, Matthias Van Hul, Anne Salonen, Patrice D. Cani
Journal: Gut Microbes (2022)

Obesity is a major risk factor for the development of type 2 diabetes and cardiovascular diseases, and gut microbiota plays a key role in influencing the host energy homeostasis. Moreover, obese mice have a different gut microbiota composition, associated with an alteration of the intestinal mucus layer, which represents the interface between the bacteria and the host. We previously demonstrated that prebiotic treatment with oligofructose (FOS) counteracted the effects of diet-induced obesity, together with changes in the gut microbiota composition, but it is not known if the intestinal mucus layer could be involved. In this study, we found that, in addition to preventing high-fat diet (HFD) induced obesity in mice, the treatment with FOS increased the expression of numerous genes involved in mucus production, glycosylation and secretion, the expression of both secreted and transmembrane mucins, and the differentiation and number of goblet cells. These results were associated with significant changes in the gut microbiota composition, with FOS significantly increasing the relative and absolute abundance of the bacterial genera Odoribacter, Akkermansia, two unknown Muribaculaceae and an unknown Ruminococcaceae. Interestingly, all these bacterial genera had a negative association with metabolic parameters and a positive association with markers of the mucus layer. Our study shows that FOS treatment is able to prevent HFD-induced metabolic disorders, at least in part, by acting on all the processes of the mucus production. These data suggest that targeting the mucus and the gut microbiota by using prebiotics could help to prevent or mitigate obesity and related disorders.
Spatially Resolved Single-Cell Assessment of Pancreatic Cancer Expression Subtypes Reveals Co-expressor Phenotypes and Extensive Intratumoral Heterogeneity
Authors: Hannah L. Williams, Andressa Dias Costa, Jinming Zhang, Srivatsan Raghavan, Peter S. Winter, Kevin S. Kapner, Scott P. Ginebaugh, Sara A. Väyrynen, Juha P. Väyrynen, Chen Yuan, Andrew W. Navia, Junning Wang, Annan Yang, Timothy L. Bosse, Radha L. Kalekar, Kristen E. Lowder, Mai Chan Lau, Dalia Elganainy, Vicente Morales-Oyarvide, Douglas A. Rubinson, Harshabad Singh, Kimberly Perez, James M. Cleary, Thomas E. Clancy, Jiping Wang, Joseph D. Mancias, Lauren K. Brais, Emma R. Hill, Margaret M. Kozak, David C. Linehan, Richard F. Dunne, Daniel T. Chang, Albert C. Koong, Aram F. Hezel, William C. Hahn, Alex K. Shalek, Andrew J. Aguirre, Jonathan A. Nowak, Brian M. Wolpin
Journal: Cancer Research (2022)

Pancreatic ductal adenocarcinoma (PDAC) has been classified into classical and basal-like transcriptional subtypes by bulk RNA measurements. However, recent work has uncovered greater complexity to transcriptional subtypes than was initially appreciated using bulk RNA expression profiling. To provide a deeper understanding of PDAC subtypes, we developed a multiplex immunofluorescence (mIF) pipeline that quantifies protein expression of six PDAC subtype markers (CLDN18.2, TFF1, GATA6, KRT17, KRT5, and S100A2) and permits spatially resolved, single-cell interrogation of pancreatic tumors from resection specimens and core needle biopsies. Both primary and metastatic tumors displayed striking intratumoral subtype heterogeneity that was associated with patient outcomes, existed at the scale of individual glands, and was significantly reduced in patient-derived organoid cultures. Tumor cells co-expressing classical and basal markers were present in > 90% of tumors, existed on a basal-classical polarization continuum, and were enriched in tumors containing a greater admixture of basal and classical cell populations. Cell-cell neighbor analyses within tumor glands further suggested that co-expressor cells may represent an intermediate state between expression subtype poles. The extensive intratumoral heterogeneity identified through this clinically applicable mIF pipeline may inform prognosis and treatment selection for patients with PDAC.
Reply to M. Baboudjian et al
Authors: Scott E. Eggener, Alejandro Berlin, Andrew J. Vickers, Gladell P. Paner, Howard Wolinsky, Matthew R. Cooperberg
Journal: Journal of Clinical Oncology (2022)

We would like to thank Baboudjian et al 1 (on behalf of the French Urology Association) for their interest in our work. 2They discuss many relevant issues which warrant clarification.First, they state that the surgeon's perspective is not well represented in this debate.Two of our authors (S.E.E., M.R
Anchoring super-enhancer-driven oncogenic lncRNAs for anti-tumor therapy in hepatocellular carcinoma
Authors: Xiao-Qing Yuan, Nan Zhou, Jun-Pu Wang, Xian-Zhu Yang, Shan Wang, Chao-Yang Zhang, Guan-Cheng Li, Li Peng
Journal: Molecular Therapy (2022)

Super-enhancer (SE) plays a vital role in the determination of cell identity and fate. Up-regulated expression of coding genes is frequently associated with SE. However, the transcription dysregulation driven by SE, from the viewpoint of long non-coding RNA (lncRNA), remains unclear. Here, SE-associated lncRNAs in HCC are comprehensively outlined for the first time. This study integrally screens and identifies several novel SE-associated lncRNAs that are highly abundant and sensitive to JQ1. Especially, HSAL3 is identified as an uncharacterized SE-driven oncogenic lncRNA, which is activated by transcription factors HCFC1 and HSF1 via its super-enhancer. HSAL3 interference negatively regulates NOTCH signaling, implying the potential mechanism of its tumor-promoting role. The expression of HSAL3 is increased in HCC samples, and higher HSAL3 expression indicates an inferior overall survival of HCC patients. Furthermore, siHSAL3 loaded nanoparticles exert anti-tumor effect on HCC in vitro and in vivo. In conclusion, this is the first comprehensive survey of SE-associated lncRNAs in HCC. HSAL3 is a novel SE-driven oncogenic lncRNA, and siHSAL3 loaded nanoparticles are therapeutic candidates for HCC. This work sheds lights on the merit of anchoring SE-driven oncogenic lncRNAs for HCC treatment. Super-enhancer (SE) plays a vital role in the determination of cell identity and fate. Up-regulated expression of coding genes is frequently associated with SE. However, the transcription dysregulation driven by SE, from the viewpoint of long non-coding RNA (lncRNA), remains unclear. Here, SE-associated lncRNAs in HCC are comprehensively outlined for the first time. This study integrally screens and identifies several novel SE-associated lncRNAs that are highly abundant and sensitive to JQ1. Especially, HSAL3 is identified as an uncharacterized SE-driven oncogenic lncRNA, which is activated by transcription factors HCFC1 and HSF1 via its super-enhancer. HSAL3 interference negatively regulates NOTCH signaling, implying the potential mechanism of its tumor-promoting role. The expression of HSAL3 is increased in HCC samples, and higher HSAL3 expression indicates an inferior overall survival of HCC patients. Furthermore, siHSAL3 loaded nanoparticles exert anti-tumor effect on HCC in vitro and in vivo. In conclusion, this is the first comprehensive survey of SE-associated lncRNAs in HCC. HSAL3 is a novel SE-driven oncogenic lncRNA, and siHSAL3 loaded nanoparticles are therapeutic candidates for HCC. This work sheds lights on the merit of anchoring SE-driven oncogenic lncRNAs for HCC treatment.
Ischemic polypectomy using a diagnostic-type double-balloon endoscope with a modified detachable snare
Authors: Yusuke Ono, Kunihiko Oguro, Tomonori Yano, Manabu Nagayama, Ulzii Dashnyam, Alan Kawarai Lefor, Hironori Yamamoto
Journal: Endoscopy (2022)

Polypectomy of small-bowel polyps larger than 10 mm is recommended in patients with Peutz-Jeghers syndrome (PJS) [1]. During double-balloon enteroscopy (DBE) for polypectomy in patients with PJS, deeper insertions are sometimes difficult owing to post-surgical adhesions. When bi-directional DBE using a therapeutic-type scope fails to reach polyps, a diagnostic-type scope with a smaller outer diameter ([Fig. 1]) is an alternative. However, a hemoclip and a detachable snare are unavailable in this scope because its outer casing is larger than the working channel (2.2 mm). Therefore, it is considered challenging to perform conventional polypectomy and ischemic polypectomy [2] [3].
Peroral endoscopic myotomy for treatment of achalasia in a patient with congenital osteogenesis imperfecta and scoliosis
Authors: Zu-Qiang Liu, Li Wang, Quan-Lin Li, Ping-Hong Zhou
Journal: Endoscopy (2022)

A 22-year-old man was admitted because of dysphagia and regurgitation for half a year. Gastroscopy showed narrowing of the cardia ([Fig. 1]) and the upper gastrointestinal series showed the "bird's beak" sign of the cardia and dilatation and distortion of the esophageal lumen ([Fig. 2]). The patient was diagnosed clinically as having achalasia. In addition, he had a previous history of osteogenesis imperfecta, a rare inherited bone disorder, from birth, with fragile bones that are easily broken. As a result, he had multiple malformations of his arms and legs, thoracocyllosis, and scoliosis, with a body weight of 55 kg and a sitting height of 50 cm ([Fig. 3]). Preoperative pulmonary function tests showed a moderate restrictive ventilatory impairment. Peroral endoscopic myotomy (POEM) was proposed after a full multidisciplinary discussion with the anesthesia, orthopedic, and respiratory departments.
Endoscopic ultrasound-guided bile duct reconstruction after complete section following a car crash in a 5-year-old child with complete situs inversus
Authors: Clara Yzet, Alexandru Lupu, Emmanuel Forté, Rémi Dubois, Eloïse Cercueil, Thierry Ponchon, Mathieu Pioche
Journal: Endoscopy (2022)

Bile duct complete section is a rare adverse event of abdominal traumatism that can appear on the upper border of the pancreas [1] [2]. We report here the case of a 5-year- old girl, with a complete situs inversus, who underwent a car crash with several injuries, including a complete section of the bile duct at the junction with the pancreas. We first attempted an endoscopic retrograde cholangiography approach (ERCP) by inverting the patient and physician position. It was technically difficult because of the inverted anatomy and the guidewire systematically went to the pancreatic duct. A surgical drain was placed in the gallbladder to reduce bile flow, but unfortunately the abdominal collection did not reduce. It finally grew to a large 15-cm collection with both pancreatic and bile juice when analyzed.
Early duodenal cancer successfully treated by endoscopic submucosal dissection with an ultra-thin endoscope in spite of severe esophageal stricture
Authors: Toshiaki Narasaka, Tsubasa Onoda, Mariko Kobayashi, Shintaro Akiyama, Taku Sakamoto, Hideo Suzuki, Kiichiro Tsuchiya
Journal: Endoscopy (2022)

We report a case of early duodenal cancer successfully treated by endoscopic submucosal dissection (ESD) using an ultra-thin endoscope in a patient with severe stricture caused by photodynamic therapy (PDT) for esophageal cancer.
A new method to identify the afferent limb in balloon enteroscopy-assisted ERCP: Retention of gel mixed with contrast medium under fluoroscopy
Authors: Koh Fukushi, Koki Hoshi, Yoko Abe, Akira Yamamiya, Kazunori Nagashima, Atsushi Irisawa
Journal: Endoscopy (2022)

In recent years, balloon enteroscopy-assisted endoscopic retrograde cholangiopancreatography (BA-ERCP) has been performed for biliary pancreatic endoscopic procedures for postoperative reconstruction of the intestinal tract. In BA-ERCP, especially in cases after Roux-en-Y anastomosis, it is often difficult to identify the afferent limb. Several methods have been reported so far [1] [2] [3]. Herein we report a new method that can discriminate more objectively.
A novel extracorporeal accessory traction device for gastric endoscopic submucosal dissection
Authors: Wen-zhe Zhai, Yan-jun Kang, Xiang-hua Wu, Xiu-li Zuo, Ai-jun Zhang, Qing Wang, Ru-yuan Li
Journal: Endoscopy (2022)

For early gastric cancer, endoscopic submucosal dissection (ESD) has been established as a standard treatment. However, ESD is associated with several complications, such as bleeding and perforation, which makes ESD difficult for entry-level operators [1]. A clear surgical view can reduce the occurrence of complications, shorten the operating time, and reduce the difficulty of the operation. As a result, various traction methods and devices have been developed and used during ESD [2]. The first author has developed a novel extracorporeal accessory traction device for gastric ESD, which in our opinion can make it easier and safer.
Refractory aortoesophageal fistulas after aortic stenting successfully closed using endoscopic submucosal dissection with clip closure
Authors: Pierre Lafeuille, Laurent Poincloux, Olivier Rouquette, Clara Yzet, Thierry Ponchon, Jérôme Rivory, Mathieu Pioche
Journal: Endoscopy (2022)

A gastrointestinal (GI) fistula is a chronic, life-threatening condition and a therapeutic challenge [1]. Endoscopic closure requires combined approaches with both mucosal ablation and mechanical closure of the fistulous tract [2]. As we recently reported in a multicenter cohort study, the novel strategy of fistula endoscopic submucosal dissection with clip closure (FESDC) is safe and feasible for permanent closure of GI fistulas [3]. This technically demanding procedure could be added to standard endoscopic strategies in first-line treatment or could be proposed as a second-line therapy when the fistula remains refractory to other current approaches [4].
Neuronal and tumourigenic boundaries of glioblastoma plasticity
Authors: Manam Inushi De Silva, Brett W. Stringer, Cedric Bardy
Journal: Trends in cancer (2022)

Glioblastoma (GBM) remains the most lethal primary brain cancer largely due to recurrence of treatment-resistant disease. Current therapies are ultimately ineffective as GBM tumour cells adapt their identity to escape treatment. Recent advances in single-cell epigenetics and transcriptomics highlight heterogeneous cell populations in GBM tumours originating from unique cancerous genetic aberrations. However, they also suggest that tumour cells conserve molecular properties of parent neuronal cells, with their permissive epigenetic profiles enabling them to morph along a finite number of reprogramming routes to evade treatment. Here, we review the known tumourigenic, neurodevelopmental and brain-injury boundaries of GBM plasticity, and propose that effective treatment of GBM requires the addition of therapeutics that restrain GBM plasticity.
Endoscopic full-thickness resection is a safe and effective method for the treatment of sigmoid schwannomas
Authors: Martina De Siena, Federico Barbaro, Luigi Giovanni Papparella, Cristina Ciuffini, Ivo Boškoski
Journal: Endoscopy (2022)

We report the case of a 49-year-old man with a distal sigmoid schwannoma that was accidentally found during a screening colonoscopy. The patient was referred to our Center for further evaluation. Endoscopic ultrasound (EUS) confirmed the presence of a sigmoid lesion showing a well-circumscribed hyperenhancing mass of 10 mm in diameter, compatible with a gastrointestinal stromal tumor. We decided to perform a full-thickness resection (FTR) of the lesion ([Video 1]). Chromoendoscopy showed the submucosal lesion located in the distal sigmoid colon, near to a previously placed endoscopic tattoo ([Fig. 1 a]). First, the edges of the lesion were marked with the FTR device (FTRD) Marking Probe (Olympus) ([Fig. 1 b]), the lesion was pull into the FTRD system set (Ovesco Endoscopy) ([Fig. 1 c]) and then removed, with placement of an over-the-scope (OTS) clip ([Fig. 1 d]). The resected lesion was recovered outside and placed on a cork for histological analysis ([Fig. 2]). No periprocedural complications were observed. Later the same day, after an adequate period of observation, the patient was discharged from our hospital in good general condition. At 3- and 6-month follow-up, rectosigmoidoscopy showed a flat and regular scar, with no macroscopic signs of residual tissue or recurrence, confirming the complete resection of the lesion.
A 3D Perfusable Platform for In Vitro Culture of Patient Derived Xenografts
Authors: Lindsey K. Sablatura, Kristin M. Bircsak, Peter Shepherd, Madhavi Bathina, Karla Queiroz, Mary C. Farach‐Carson, Rick A. Kittles, Pamela E. Constantinou, Anthony Saleh, Nora M. Navone, Daniel A. Harrington
Journal: Advanced Healthcare Materials (2022)

Many advanced cancer models, such as patient-derived xenografts (PDXs), offer significant benefits in their preservation of the native tumor's heterogeneity and susceptibility to treatments, but face significant barriers to use in their reliance on a rodent host for propagation and screening. PDXs remain difficult to implement in vitro, particularly in configurations that enable both detailed cellular analysis and high-throughput screening (HTS). Complex multilineage co-cultures with stromal fibroblasts, endothelium, and other cellular and structural components of the tumor microenvironment (TME) further complicate ex vivo implementation. Herein, the culture of multiple prostate cancer (PCa)-derived PDX models as 3D clusters within engineered biomimetic hydrogel matrices, in a HTS-compatible multiwell microfluidic format, alongside bone marrow-derived stromal cells and a perfused endothelial channel. Polymeric hydrogel matrices are customized for each cell type, enabling cell survival in vitro and facile imaging across all conditions. PCa PDXs demonstrate unique morphologies and reliance on TME partners, retention of known phenotype, and expected sensitivity or resistance to standard PCa therapeutics. This novel integration of technologies provides a fully human model, and expands the information to be gathered from each specimen, while avoiding the time and labor involved with animal-based testing.